EP2265283B1 - Auristatin drug linker conjugates - Google Patents

Auristatin drug linker conjugates Download PDF

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Publication number
EP2265283B1
EP2265283B1 EP09721267.4A EP09721267A EP2265283B1 EP 2265283 B1 EP2265283 B1 EP 2265283B1 EP 09721267 A EP09721267 A EP 09721267A EP 2265283 B1 EP2265283 B1 EP 2265283B1
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Prior art keywords
group
alkyl
antibody
drug
unit
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EP09721267.4A
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German (de)
English (en)
French (fr)
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EP2265283A4 (en
EP2265283A1 (en
Inventor
Peter Senter
Svetlana Doronina
Timothy Bovee
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Seagen Inc
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Seattle Genetics Inc
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Priority to DK14182732.9T priority Critical patent/DK2842575T3/da
Priority to PL14182732T priority patent/PL2842575T3/pl
Priority to EP14182732.9A priority patent/EP2842575B1/en
Priority to NO14182732A priority patent/NO2842575T3/no
Priority to PL09721267T priority patent/PL2265283T3/pl
Publication of EP2265283A1 publication Critical patent/EP2265283A1/en
Publication of EP2265283A4 publication Critical patent/EP2265283A4/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
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    • A61K47/6861—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from kidney or bladder cancer cell
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6865—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from skin, nerves or brain cancer cell
    • A—HUMAN NECESSITIES
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6867—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P37/00—Drugs for immunological or allergic disorders
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
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Definitions

  • trade name includes the product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product, unless otherwise indicated by context.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized ( i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already having the condition or disorder as well as those prone to have the condition or disorder.
  • a nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence.
  • DNA for a presequence or secretory leader is operably linked to DNA encoding a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide;
  • a promoter or enhancer is operably linked to a coding sequence, for example, if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation.
  • "operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking can be accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers can be used in accordance with conventional practice.
  • alkyl by itself or as part of another term refers to a substituted or unsubstituted a straight chain or branched, saturated or unsaturated hydrocarbon having the indicated number of carbon atoms (e.g., "-C 1 -C 8 alkyl” or “-C 1 -C 10 " alkyl refer to an alkyl group having from 1 to 8 or 1 to 10 carbon atoms, respectively). When the number of carbon atoms is not indicated, the alkyl group has from 1 to 8 carbon atoms.
  • Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • a "C 3 -C 8 carbocycle" group can be unsubstituted or substituted with one or more groups including, but not limited to, -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH 2 , -C(O)NHR', -C(O)N(R') 2 , NHC(O)R', -S(O) 2 R', -S(O)R', -OH, -halogen, -N 3 , -NH 2 , -NH(R'), -N(R') 2 and -CN; where each R' is independently selected from -H, -C 1 -C 8 alkyl and aryl.
  • Boc is N -( t -butoxycarbonyl), cit is citrulline, dap is dolaproine, DCM is dichloromethane, DIEA is N,N -diisopropylethylamine, dil is dolaisoleuine, DMF is N,N -dimethylformamide, DMSO is dimethylsulfoxide, doe is dolaphenine, dov is N,N -dimethylvaline, DTNB is 5,5'-dithiobis(2-nitrobenzoic acid), DTPA is diethylenetriaminepentaacetic acid, DTT is dithiothreitol, Fmoc is N -(9-fluorenylmethoxycarbonyl), gly is glycine, HATU is O -(7-azabenzotriazol-1-yl)- N,N,N',N' -tetramethyluronium
  • cytotoxic drug abbreviations are used herein and have the indicated definitions: "Auristatin F” or “AF” is N,N-dimethylvaline-valine-dolaisoleuine(dil)-dolaproine(dap)-phenylalanine. "MMAF” is N-methylvaline-valine-dolaisoleuine(dil)-dolaproine(dap)-phenylalanine (MW 731.5).
  • R 3 is -H or -C 1 -C 8 saturated alkyl
  • R 4 is a side chain of a natural amino acid
  • R 6 is -H or -C 1 -C 8 saturated alkyl
  • R 7 is -H or C 1 -C 8 saturated alkyl
  • R 8 is -O-(C 1 -C 8 saturated alkyl) and the remaining groups are as indicated herein.
  • R 1 and R 2 are -H or-C 1 -C 8 unsubstituted saturated alkyl with the proviso that both are not hydrogen
  • R 3 is -H or -C 1 -C 8 unsubstituted saturated alkyl
  • R 4 is a side chain of a natural amino acid
  • R 6 is -H or -C 1 -C 8 unsubstituted saturated alkyl
  • R 7 is -H or -C 1 -C 8 unsubstituted saturated alkyl
  • R 8 is -O-(C 1 -C 8 unsubstituted saturated alkyl) and the remaining groups are as indicated herein.
  • sulfhydryl groups can be generated by reaction of an amino group of a lysine moiety of a Ligand unit using 2-iminothiolane (Traut's reagent) or another sulfhydryl generating reagent.
  • the Stretcher unit forms a bond with a sulfur atom of the Ligand unit.
  • the sulfur atom can be derived from a sulfhydryl group of a Ligand unit.
  • Representative Stretcher units of this embodiment are depicted within the square brackets of Formulas IIIa and IIIb, wherein L-, -W-, -D, w and p are as defined above, and R 9 can be selected from the group consisting of -C 1 -C 10 alkylene-, -C 3 -C 8 carbocyclo-, -arylene-, -C 1 -C 30 heteroalkylene-, -C 3 -C 8 heterocyclo-, -C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, -C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, -(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-
  • -O-R 9 - is selected from -O-C 1 -C 10 alkylene-, -O-C 1 -C 10 alkylene-NH-C(O)-C 1 -C 10 alkylene-, -O-C 1 -C 10 alkylene-C(O)-NH-C 1 -C 10 alkylene-, -O-(CH 2 CH 2 O) r -, O-(CH 2 CH 2 O) r -CH 2 -, -O-(C 3 -C 8 carbocyclo)-, -O-(arylene)-, and -O-(C 3 -C 8 heterocyclo-)-, wherein each r is independently 1-10.
  • Another illustrative Stretcher unit is that of the following Formula IIIb, wherein R 9 is -C 1 -C 30 heteroalkylene-:
  • aspartic acid and derivatives thereof include but are not limited to: aspartic acid (Asp), N-alkyl-aspartic acid, and H-Asp(OtBu)-OH.
  • glutamine and derivatives thereof include but are not limited to: glutamine (Gln), N-alkyl-glutamine, isoglutamine (H-Glu-NH 2 ), H-Gln(Trt)-OH, and H-Gln(isopropyl)-OH.
  • an aminoalkanoic acid and derivatives thereof include but are not limited to: N-alkylaminoalkanoic acid, aminobutyric acid, 4-(neopentyloxysulfonyl)-aminobutyric acid, ⁇ -aminocaproic acid, ⁇ -aminoisobutyric acid, piperidylacetic acid, 3-aminopropionic acid, 3-amino-3-(3-pyridyl)-propionic acid, and 5-aminopentanioic acid (aminovaleric acid).
  • an amino-heterocyclo-alkanoic acid and derivatives thereof include but are not limited to: N-alkylamino-heterocyclo-alkanoic acids, 4-amino-1-methyl-1H-imidazol-2-carboxylic acid, 4-amino-1-methyl-1H-pyrrole-2-carboxylic acid, 4-amino-piperidine-4-carboxylic acid (H-Pip-OH; 1-protected or not), 3-amino-3-(3-pyridyl)-propionic acid.
  • Useful polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of immunized animals.
  • Useful monoclonal antibodies are homogeneous populations of antibodies to a particular antigenic determinant (e.g ., a cancer cell antigen, a viral antigen, a microbial antigen, a protein, a peptide, a carbohydrate, a chemical, nucleic acid, or fragments thereof).
  • a monoclonal antibody (mAb) to an antigen-of-interest can be prepared by using any technique known in the art which provides for the production of antibody molecules by continuous cell lines in culture.
  • antibodies for the treatment of cancer can be used.
  • Antibodies immunospecific for a cancer cell antigen can be obtained commercially or produced by any method known to one of skill in the art such as, e.g ., recombinant expression techniques.
  • the nucleotide sequence encoding antibodies immunospecific for a cancer cell antigen can be obtained, e.g ., from the GenBank database or a database like it, the literature publications, or by routine cloning and sequencing.
  • TNF receptor superfamily members are CD27, CD40, CD95/Fas, CD134/0X40, CD137/4-1BB, TNF-R1, TNFR-2, RANK, TACI, BCMA, osteoprotegerin, Apo2/TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4, and APO-3.
  • suitable integrins are CD11a, CD11b, CD11c, CD18, CD29, CD41, CD49a, CD49b, CD49c, CD49d, CD49e, CD49f, CD103, and CD104.
  • suitable lectins are C-type, S-type, and I-type lectin.
  • microbial antigen includes, but is not limited to, any microbial peptide, polypeptide, protein, saccharide, polysaccharide, or lipid molecule (e.g., a bacterial, fungi, pathogenic protozoa, or yeast polypeptide including, e.g., LPS and capsular polysaccharide 5/8) that is capable of eliciting an immune response.
  • microbial antigen includes, but is not limited to, any microbial peptide, polypeptide, protein, saccharide, polysaccharide, or lipid molecule (e.g., a bacterial, fungi, pathogenic protozoa, or yeast polypeptide including, e.g., LPS and capsular polysaccharide 5/8) that is capable of eliciting an immune response.
  • Also described is a screening method comprising (a) contacting cells from a stable Hodgkin's disease cell line with an ADC drug candidate and (b) evaluating the ability of the ADC candidate to induce cell death. In one embodiment the ability of the ADC candidate to induce apoptosis is evaluated.
  • the in vitro potency of antibody drug conjugates is measured by a cell proliferation assay (see Examples).
  • the CellTiter-Glo ® Luminescent Cell Viability Assay is a commercially available (Promega Corp., Madison, WI), homogeneous assay method based on the recombinant expression of Coleoptera luciferase ( U.S. Patent Nos. 5,583,024 ; 5,674,713 and 5,700,670 ).
  • This cell proliferation assay determines the number of viable cells in culture based on quantitation of the ATP present, an indicator of metabolically active cells ( Crouch et al., 1993, J. Immunol. Meth. 160:81-88 , U.S. Patent No. 6,602,677 ).
  • Enzymes indicative of liver injury that are studied include:
  • the heteroatom of the nucleophilic group of an antibody is reactive to an electrophilic group on a Linker unit and forms a covalent bond to a Linker unit.
  • Useful electrophilic groups include, but are not limited to, maleimide and haloacetamide groups.
  • the electrophilic group provides a convenient site for antibody attachment.
  • Drug Linker compounds containing more that 2 amino acids in the Linker unit were prepared by incorporating additional steps (b), (c) with Fmoc-W 3
  • a variety of ADCs can be prepared, with a variety of linkers and a variety of drug moieties, by following the protocols of the Examples, and characterized by HPLC and drug loading assay.
  • compositions can be in any form that allows for the composition to be administered to a patient.
  • the composition can be in the form of a solid or liquid.
  • Typical routes of administration include, without limitation, parenteral, ocular and intra-tumor.
  • Parenteral administration includes subcutaneous injections, intravenous, intramuscular or intrasternal injection or infusion techniques.
  • the compositions may be administered parenterally. Alternatively the compositions are administered intravenously.
  • the amount of the Drug Linker Ligand conjugate and/or a Drug Linker compound that is effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances.
  • the Drug Linker Ligand conjugates and Drug Linker compounds are useful for inhibiting the multiplication of a tumor cell or cancer cell, causing apoptosis in a tumor or cancer cell, or for treating cancer in a patient.
  • the Drug Linker Ligand conjugates and/or Drug Linker compounds can be used accordingly in a variety of settings for the treatment of animal cancers.
  • the Drug Linker Ligand Conjugates can be used to deliver a Drug or Drug unit to a tumor cell or cancer cell.
  • AF-Asparagine-(D)Aspartic Acid-diaminoethane-propionyl maleimide ( 7f ) was prepared using the same method as 5c starting with 100 mg of Fmoc-(D)Asp(OtBu)-diaminoethane-trityl resin ( 3 ), and using Fmoc-Asn(trt) as AA1. Yield: 38 mg (49%) of white solid.
  • RP-HPLC analysis: >90% at 10.85 min; ESMS m/z 1167.075 (M+H) + .
  • AF-Methionine-(D)Valine-diaminoethane-propionyl maleimide 8s was prepared in the same manner as 5c, starting with 156 mg of Fmoc-(D)Valine-diaminoethane trityl resin ( 1a ), and using Fmoc-Met for AA1. Yield: 13 mg (13%).
  • AM-Asn-(D)Lys conjugates had similar in vitro potency as corresponding MC-MMAF conjugates.
  • AW-Met-(D)Lys conjugates appear to be less active.
  • Table 11 Summary of IC50s (ng/mL) for selected Aurisiatin-peptide conjugates with cAC10, hBU12, Anti-LIV-1, and BR96 antibodies.

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